20, 21-diacetoxy-4-bromo-3, 11-diketopregnanes



Patented Aug. 22,1950 V I UNITED STATES PATENT OFF lCEf 20,21 -DIA'GETOXY -4 -BROMO -3,11 -DIKETO PREGNANES Lewis H. Sarett, Princeton, N. J.., assi'gnor to Merck & 00., Inc., Rahway, N. J.,;a corporation of New Jersey No Drawing. Application August 2', 1946, Serial No. 687,983

3 Claims. (01. 260-3914) 1'. 2 This invention is concernedgenerally with In the following description of the invention, novel chemical compounds of the cyclopentanothe stereochemical relationsof" the substituents dimethylpolyhydrophenanthrene --series and to are indicated by the following conventionsz processes of preparing the same; more partic- (1) A substituent at the C20 position: is arbiularly, it relates to stereoisomers of bromo- 5 trarily indicated as a or 18 depending upon the 3,11-diketo 20,21 diacyloxypregnane and to stereochemical configuration thereof; in: this apmethods for preparing these stereoisomers from plication the convention is adopted! that the conreadily awaila'lo'lestartingmaterials;v These. comfiguration is represented by writing the C20 subpe'unds are useful in the preparation: of: adrenali stituent (acyloxy) at the right. of th p Hormones such as: dehydrocorticosterone -and side chain thus; esters-thereof; and fcr other-purposes They are also of -value as a means of establishing the CHQOR structure of other organiccompcunds:

These-1 stereoisomeric 4-br omo-3,1I diketol 20321 diacy-loX -pregnanes v can 'be. represented:

bythe-followingstructural formulae: and in the case of the epimeric a configuration,

21 onion. onion zone-c n" H2 HC OR o 5 13H CH 2- 12 1-7.- 0 c CH 1s" ci1 were Hz CH3 1 1 2 m 0H3: 1 ml 0 I no H cm or Ho GH-GHz-' /1\ /9.\; H= 32 A 10 B so 0:0 H2 0=C3\4:/5+\6/7%}H2- \G/]{\O H cm: r 7 Br wherein.R;.-is-acy1. the swbsti-tuent is written to the left of the side Thesaiormulae for purposes; of: convenience, chain thus a'reshereinaiter'reproduced below in theahlorevieated form:

ofiaon onion 35 RO Y. H H OH GHzOR' CH3 CH3 R0- |3 -H r 0 (2) The stereochemical relations of ringsHA.

H figuration. 1 Br In: accordance. with the priesentuinvention, ituis and B is-indicated in the formulae by a solidlinef representing the valence bond in the eis con-= whereinrm lias thesignifi'canceabove: defined. i now" found. that 4-brom03;li diketo-2o ziediea acyloxypregnanes can be synthesized by reactions indicated generically as follows:

CHaO R R 37-11 CH2 CH1 Brominating '-r agent (111120 R R 0-CH CH3 CH:

OHIO R H- O H CH1 CH3 Brominating agent H- O R CH3 CH3 H B r in the above formulae R is acyl.

The reactions indicated above are conducted as follows:

A stereoisomer of 3,11-diketo-20,2l-diacyloxypregnane (1 and 2) or a mixture of stereoisomers thereof, which can be prepared as disclosed in my copending applications, Serial No. 649,760, filed February 23, 1946 (which is a continuation-inpart of application Serial No, 605,194, filed July 13, 1945, now abandoned) Serial No. 687,982, filed August 2, 1946, noW Patent No. 2,505,838; and Serial No. 687,980, filed August 2, 1946, now Patent No. 2,516,258; is reacted with a brominating agent to produce the corresponding stereoisomer, or mixtures of stereoisomers, of 4-bromo-3,11- diketo-20,2l-diacyloxypregnane (3 and 4). This product can be converted to an ester of dehydrocorticosterone according to processes disclosed in my copending application, Serial No. 687,981 filed August 2, 1946, now Patent No. 2,510,940,

In accordance with the present invention, a stereolsomer of 3,1l-diketo-20,21-diacy1oxy-pregnane, as for example 3,11-diketo-20-(u)21-diacetoxy-pregnane; 3,11-diketo-20- (c) -21-diacetoxy-pregnane; 3,11-diketo-20- (a) -2l-dipropionoxy-pregnane; 3,11-diketo-20- 8) -21-dipropionoxy-pregnane; 3,11 diketo (a) 21-dibutyroxypregnane; 3,11 diketo 20-(,B) -21-dibutyroxypregnane; 3,11 diKGtO-ZO-(a) -21-dibenzoxypregnane; 3,11 diketo 20 (,6) -21-dibenzoxypregnane; or mixtures thereof, is reacted with a substantially equimolecular quantity of bromine in an inert solvent such as glacial acetic acid.

It is important not to use substantially more than an equimolecular quantity of bromine be cause the use of an excess favors the formation of the dihalide. The bromine enters the molecule at the 4-position to form the corresponding stereoisomer of 4-bromo-3,11-diketo-20,21-diacyloxy-pregnane, which can be represented by the following structural formula:

7 CHzOR OH: HOR

H Br wherein R is acyl.

In applicants preferred procedure, 3,11-diketo- 20,21-diacyloxy pregnanes are reacted with bromine in glacial acetic acid, after which the product is isolated as follows: The reactant is dissolved in a solvent such as ether, the ether solution washed with a dilute alkaline solution containing an alkali or alkaline earth hydroxide or carbonate, whereby acidic materials are removed from the ether solution which is evaporated to dryness under reduced pressure, and the product can be purified if desired by recrystallization from an aliphatic alcohol, such as ethyl alcohol to produce the corresponding 4-bromo- 3,11-diketo-20,21-diacyloxy-pregnane.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1 About 663 mg. of 3,11-diketo-20-(c) -21-diacetoxy-pregnane is dissolved in about 25 cc. of glacial acetic acid and a solution containing about 260 mg. of bromine in about 2.6 cc. of glacial acetic acid is added thereto. The bromine is decolorized after a few minutes and the solution is then poured into a mixture of chloroform and dilute aqueous sodium bicarbonate solution. The mixture is shaken, the chloroform layer separated and washed with water and evaporated to dryness under reduced pressure to produce amorphous 4-bromo-3,11-diketo-20-(p) -21-diacetoxypregnane.

Example 2 About 703 mg. of 3,lldiketo-20-(a) -diacetoxypregnane is dissolved in about 2.8 cc. of glacial acetic acid and a solution containing about 276 mg. of bromine in about 2.76 cc. of glacial acetic acid is added thereto. After decolorization, the product is isolated as described in Example 1 to 5 produce amorphous 4-b10m0-3,11-diket020-(a) ZI-diacetoxy-pregnane.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

Iclaim:

1. 20,21 diacetoxy-4-bromo-3,1l-diketo-pregnames.

2. 4 bromo-3,11-diketo-20-(a)-21-diacetoxypregnane.

6 3. 4 bromo-3,11-diketo-20-(p)-21-diacetoxypregnane.

LEWIS H. SAREFIT.

5 REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Serini Sept. 23, 1941 10 Number Certificate of Correction Patent No. 2;5l9,507 August 22, 1950 LEWIS H. SARETT It is hereby certified that error appears in the printed specification of the above numbered patent requiring correctlon as follows:

Column 3, lines 62 and 63, for the filing date July 13, 194:5 read July 14, 1.945 column 4, line 56, for 25 cc. read 2.5 00.

and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 12th day of December, A. D. 1950.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. 20,21 - DIACETOXY-4-BROMO-3,11-DIKETO-PREGNANES. 